doi:10.1093/nar/gkp471 Stochastic noise in splicing machinery

The number of known alternative human isoforms has been increasing steadily with the amount of available transcription data. To date, over 100 000 isoforms have been detected in EST libraries, and at least 75 % of human genes have at least one alternative isoform. In this paper, we propose that most alternative splicing events are the result of noise in the splicing process. We show that the number of isoforms and their abundance can be predicted by a simple stochastic noise model that takes into account two factors: the number of introns in a gene and the expression level of a gene. The results strongly support the hypothesis that most alternative splicing is a consequence o

BIOINFORMATIC ANALYSIS OF THE FUNCTIONAL AND STRUCTURAL IMPLICATIONS OF ALTERNATIVE SPLICING.

In higher Eukaryotes, upon transcription of a gene, a complex set of reactions take place to remove fragments of a sequence (introns) from transcribed RNA. A large macro-molecular machine (the spliceosome) recognizes the ends of introns, brings ends into close proximity and catalyzes the splicing reaction. The selection of the location of the ends of introns (splice sites) determines the final message produced at the end of the process. In some cases, an alternative set of splice sites are chosen, and as a consequence different message is produced. This phenomenon is known as alternative splicing. It is now realized that nearly every Human gene undergoes alternative splicing, producing large variability in types and number of transcripts produced. In this thesis, we examine the functional and structural consequences of alternative splicing on proteins, we look into the mechanism of formation of complex splicing patterns, and examine the role of noise in the process

SNPs3D: Candidate gene and SNP selection for association studies

The relationship between disease susceptibility and genetic variation is complex, and many different types of data are relevant. We describe a web resource and database that provides and integrates as much information as possible on disease/gene relationships at the molecular level. The resource http://www.SNPs3D.org has three primary modules. One module identifies which genes are candidates for involvement in a specified disease. A second module provides information about the relationships between sets of candidate genes. The third module analyzes the likely impact of non-synonymous SNPs on protein function. Disease/candidate gene relationships and gene-gene relationships are derived from the literature using simple but effective text profiling. SNP/protein function relationships are derived by two methods, one using principles of protein structure and stability, the other based on sequence conservation. Entries for each gene include a number of links to other data, such as expression profiles, pathway context, mouse knockout information and papers. Gene-gene interactions are presented in an interactive graphical interface, providing rapid access to the underlying information, as well as convenient navigation through the network. Use of the resource is illustrated with aspects of the inflammatory response and hypertension. The combination of SNP impact analysis, a knowledge based network of gene relationships and candidate genes, and access to a wide range of data and literature allow a user to quickly assimilate available information, and so develop models of gene-pathway-disease interaction.https://doi.org/10.1186/1471-2105-7-16

SNPs3D: Candidate gene and SNP selection for association studies

The relationship between disease susceptibility and genetic variation is complex, and many different types of data are relevant. We describe a web resource and database that provides and integrates as much information as possible on disease/gene relationships at the molecular level. The resource http://www.SNPs3D.org has three primary modules. One module identifies which genes are candidates for involvement in a specified disease. A second module provides information about the relationships between sets of candidate genes. The third module analyzes the likely impact of non-synonymous SNPs on protein function. Disease/candidate gene relationships and gene-gene relationships are derived from the literature using simple but effective text profiling. SNP/protein function relationships are derived by two methods, one using principles of protein structure and stability, the other based on sequence conservation. Entries for each gene include a number of links to other data, such as expression profiles, pathway context, mouse knockout information and papers. Gene-gene interactions are presented in an interactive graphical interface, providing rapid access to the underlying information, as well as convenient navigation through the network. Use of the resource is illustrated with aspects of the inflammatory response and hypertension. The combination of SNP impact analysis, a knowledge based network of gene relationships and candidate genes, and access to a wide range of data and literature allow a user to quickly assimilate available information, and so develop models of gene-pathway-disease interaction.https://doi.org/10.1186/1471-2105-7-16

EpiFire: An Open Source C++ Library and Application for Contact Network Epidemiology

Background: Contact network models have become increasingly common in epidemiology, but we lack a flexible programming framework for the generation and analysis of epidemiological contact networks and for the simulation of disease transmission through such networks. Results: Here we present EpiFire, an applications programming interface and graphical user interface implemented in C++, which includes a fast and efficient library for generating, analyzing and manipulating networks. Network-based percolation and chain-binomial simulations of susceptible-infected-recovered disease transmission, as well as traditional non-network mass-action simulations, can be performed using EpiFire. Conclusions: EpiFire provides an open-source programming interface for the rapid development of network models with a focus in contact network epidemiology. EpiFire also provides a point-and-click interface for generating networks, conducting epidemic simulations, and creating figures. This interface is particularly useful as a pedagogical tool

Riboneogenesis in Yeast

SummaryGlucose is catabolized in yeast via two fundamental routes, glycolysis and the oxidative pentose phosphate pathway, which produces NADPH and the essential nucleotide component ribose-5-phosphate. Here, we describe riboneogenesis, a thermodynamically driven pathway that converts glycolytic intermediates into ribose-5-phosphate without production of NADPH. Riboneogenesis begins with synthesis, by the combined action of transketolase and aldolase, of the seven-carbon bisphosphorylated sugar sedoheptulose-1,7-bisphosphate. In the pathway's committed step, sedoheptulose bisphosphate is hydrolyzed to sedoheptulose-7-phosphate by the enzyme sedoheptulose-1,7-bisphosphatase (SHB17), whose activity we identified based on metabolomic analysis of the corresponding knockout strain. The crystal structure of Shb17 in complex with sedoheptulose-1,7-bisphosphate reveals that the substrate binds in the closed furan form in the active site. Sedoheptulose-7-phosphate is ultimately converted by known enzymes of the nonoxidative pentose phosphate pathway to ribose-5-phosphate. Flux through SHB17 increases when ribose demand is high relative to demand for NADPH, including during ribosome biogenesis in metabolically synchronized yeast cells

Coupling of DNA binding and helicase activity is mediated by a conserved loop in the MCM protein

Minichromosome maintenance (MCM) helicases are the presumptive replicative helicases, thought to separate the two strands of chromosomal DNA during replication. In archaea, the catalytic activity resides within the C-terminal region of the MCM protein. In Methanothermobacter thermautotrophicus the N-terminal portion of the protein was shown to be involved in protein multimerization and binding to single and double stranded DNA. MCM homologues from many archaeal species have highly conserved predicted amino acid similarity in a loop located between β7 and β8 in the N-terminal part of the molecule. This high degree of conservation suggests a functional role for the loop. Mutational analysis and biochemical characterization of the conserved residues suggest that the loop participates in communication between the N-terminal portion of the helicase and the C-terminal catalytic domain. Since similar residues are also conserved in the eukaryotic MCM proteins, the data presented here suggest a similar coupling between the N-terminal and catalytic domain of the eukaryotic enzyme